The structure of Abeta42 C-terminal fragments probed by a combined experimental and theoretical study.
The structure of Abeta42 C-terminal fragments probed by a combined experimental and theoretical study.
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DOI：
10.1016/j.jmb.2009.01.029
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发表时间：
2009-03-27
影响因子：
5.6
通讯作者：
Bowers, Michael T.
中科院分区：
文献类型：
--
作者：
Wu, Chun;Murray, Megan M.;Bernstein, Summer L.;Condron, Margaret M.;Bitan, Gal;Shea, Joan-Emma;Bowers, Michael T.
Aβ42的C端在该蛋白的寡聚化中起重要作用，因此可能是治疗阿尔茨海默病的良好治疗靶点。已证明Aβ42的某些C末端片段（CTF）可破坏寡聚化并强烈抑制Aβ42诱导的神经毒性。本文采用复制交换分子动力学（REMD）模拟和离子迁移质谱（IM-MS）研究了所选CTF（Aβ（x-42），x=29-31，39）的结构。我们在显式溶剂中的模拟结果表明，CTFs采用亚稳态β结构：Aβ的β-发夹（x-42），x=29-31，Aβ的β-链（39-42）。当最后两个疏水残基被去除时，Aβ（30-42）的β-发夹转化为卷曲构象，表明I41和A42在稳定Aβ42衍生的CTF中的β-发夹中至关重要。在IM-MS实验和无溶剂REMD模拟中进一步强调了溶剂在确定CTF结构中的重要性。比较有溶剂和无溶剂的结构表明，疏水相互作用对β-发夹的形成至关重要。CTFs在破坏寡聚化中可能发挥的作用进行了讨论。
The C-terminus of Aβ42 plays an important role in this protein's oligomerization and may therefore be a good therapeutic target for treatment of Alzheimer's disease. Certain C-terminal fragments (CTFs) of Aβ42 have been shown to disrupt oligomerization and strongly inhibit Aβ42-induced neurotoxicity. Here we study the structures of selected CTFs (Aβ(x-42), x=29-31, 39) using replica exchange molecular dynamics (REMD) simulations and ion mobility mass spectrometry (IM-MS). Our simulations in explicit solvent reveal that the CTFs adopt a metastable β-structure: β-hairpin for Aβ(x-42), x=29-31 and extended β-strand for Aβ(39-42). The β-hairpin of Aβ(30-42) is converted into a turn-coil conformation when the last two hydrophobic residues are removed, suggesting that I41 and A42 are critical in stabilizing the β-hairpin in the Aβ42-derived CTFs. The importance of solvent in determining the structure of the CTFs is further highlighted in the IM-MS experiments and solvent free REMD simulations. A comparison between the structures with and without solvent reveals that hydrophobic interactions are critical for the formation of β-hairpin. The possible role played by the CTFs in disrupting oligomerization is discussed.
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影响因子：
15
作者：
Bernstein, SL;Wyttenbach, T;Bowers, MT
通讯作者：
Bowers, MT
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
DOI：
10.1073/pnas.0702669104
发表时间：
2007-08-14
影响因子：
11.1
作者：
Dong, Jijun;Canfield, Jeffrey M.;Lynn, David G.
通讯作者：
Lynn, David G.
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG